This research program addresses basic molecular and physiological processes of nociceptive transmission in the central nervous system. The molecular research is performed in animal models, concentrating on the dorsal spinal cord because it is the first site of synapic processing for nociceptive information processing and has been identified as a locus of neuronal plasticity and altered gene expression in persistent pain states. Neurons in the dorsal horn are known to undergo marked changes in the expression of genes coding for transcriptional regulatory proteins and the precursor proteins for opioid and other neuropeptides. Our focus, using both in vitro and in vivo approaches, has been on the molecular processes that regulate the prodynorphin opioid gene. Peripheral inflammation, for example, greatly increases the expression of the dynorphin gene in spinal cord neurons specifically related to pain processing. Current studies are using adenovirus vectors to produce high levels of neuronal gene transfer and expression over a period of weeks which permits testing the efficacy of gene transfer and its effects on dynorphin expression and nociception. Studies related to higher CNS pain processing is performed with humans using in vivo brain imaging of chronic pain patients and normal volunteers to define the neural networks that subserve pain, the interaction between these networks, and the functional abnormalities induced by chronic pain in select patient populations. Methods are used which make a correlation between regional brain activation with subjects' rating of pain intensity and pain unpleasantness to better characterize the roles of specific brain areas or networks in the pain experience. The program also investigates novel methods for controlling nociceptive transmission including in vivo gene transfer to alter spinal cord receptors that transduce nociceptive stimuli. Another approach is examining recombinant cytotoxic toxin-ligand fusion proteins as a means to kill spinal cord neurons involved in pain transmission.